The HLA-D region was exhaustively studied by three techniques. The classical HLA-D typing by homozygous cells, the secondary MLR using primed lymphocyte cells (PLT) and the B cell serology detecting the DR determinant. It was shown that Dw discrepancies are necessary for the primary MLR, while the DRw difference governs the secondary MLR. Dw and DRw are thus distinct determinants possibly on the same molecule or on distinct molecules. The DR incompatibilities have a striking influence on the skin graft survival which is independent from any HLA-B linkage disequilibrium. They seem to be important targets in transplantation.